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http://hdl.handle.net/10261/63184
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dc.contributor.author | López-Atalaya, José P. | - |
dc.contributor.author | Roussel, Benoit D. | - |
dc.contributor.author | Levrat, Denis | - |
dc.contributor.author | Parcq, Jérôme | - |
dc.contributor.author | Nicole, Olivier | - |
dc.contributor.author | Hommet, Yannick | - |
dc.contributor.author | Benchenane, Karim | - |
dc.contributor.author | Castel, Hervé | - |
dc.contributor.author | Leprince, Jérôme | - |
dc.contributor.author | To Van, Denis | - |
dc.contributor.author | Bureau, Ronan | - |
dc.contributor.author | Rault, Sylvain | - |
dc.contributor.author | Vaudry, Hubert | - |
dc.contributor.author | Petersen, Karl-Uwe | - |
dc.contributor.author | Oliveira Santos, Jana Sopkova de | - |
dc.contributor.author | Ali, Carine | - |
dc.contributor.author | Vivien, Denis | - |
dc.date.accessioned | 2012-12-18T13:46:51Z | - |
dc.date.available | 2012-12-18T13:46:51Z | - |
dc.date.issued | 2008 | - |
dc.identifier | doi: 10.1038/jcbfm.2008.14 | - |
dc.identifier | issn: 0271-678X | - |
dc.identifier | e-issn: 1559-7016 | - |
dc.identifier.citation | Journal of Cerebral Blood Flow and Metabolism 28(6): 1212-1221 (2008) | - |
dc.identifier.uri | http://hdl.handle.net/10261/63184 | - |
dc.description.abstract | Current thrombolytic therapy for acute ischemic stroke with tissue-type plasminogen activator (tPA) has clear global benefits. Nevertheless, evidences argue that in addition to its prohemorrhagic effect, tPA might enhance excitotoxic necrosis. In the brain parenchyma, tPA, by binding to and then cleaving the amino-terminal domain (ATD) of the NR1 subunit of N-methyl-D-aspartate (NMDA) glutamate receptors, increases calcium influx to toxic levels. We show here that tPA binds the ATD of the NR1 subunit by a two-sites system (KD=24 nmol/L). Although tenecteplase (TNK) and reteplase also display two-sites binding profiles, the catalytically inactive mutant TNKS478A displays a one-site binding profile and desmoteplase (DSPA), a kringle 2 (K2) domain-free plasminogen activator derived from vampire bat, does not interact with NR1. Moreover, we show that in contrast to tPA, DSPA does not promote excitotoxicity. These findings, together with three-dimensional (3D) modeling, show that a critical step for interaction of tPA with NR1 is the binding of its K2 domain, followed by the binding of its catalytic domain, which in turn cleaves the NR1 subunit at its ATD, leading to a subsequent potentiation of NMDA-induced calcium influx and neurotoxicity. This could help design safer new generation thrombolytic agents for stroke treatment. © 2008 ISCBFM All rights reserved. | - |
dc.description.sponsorship | This work was supported by grants from INSERM, the French Ministry of Research and Technology, the Regional Council of Lower Normandy, the Regional Platform for Cell Imaging of Upper Normandy, the Medical Research Foundation, the University of Caen, Fonds Europeéns de Développement Régional, the Paul Hamel Foundation, the Diagnosis in Molecular Imaging Program (FP6-project DiMI-LSHB-CT-2005-512146-), and PAION Deutschland GmbH. | - |
dc.language.iso | eng | - |
dc.publisher | Lippincott Williams & Wilkins | - |
dc.rights | closedAccess | - |
dc.title | Toward safer thrombolytic agents in stroke: Molecular requirements for NMDA receptor-mediated neurotoxicity | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1038/jcbfm.2008.14 | - |
dc.date.updated | 2012-12-18T13:46:51Z | - |
dc.description.version | Peer Reviewed | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | No Fulltext | - |
item.languageiso639-1 | en | - |
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